Imaging-based metrics have recently played a central role in the quest to identify COPD phenotypes, serving to establish homogeneous sub-populations to aid in genotyping, therapeutic targeting and design and outcomes assessment. Recent findings in both animals and humans have lead us to believe that CT derived perfusion (PBF) and mean transit time (MTT) measures within regionally injured lung parenchyma provide for a functional phenotype of which may be directly tied to the etiology of the pathologic process leading to emphysema in acentrilobular emphysema susceptible subset of the smoking population. The primary hypotheses of the proposal are built around the notion that smokers prone to emphysema have abnormal vasoregulation in that regional hypoxic pulmonary vasoconstriction (HPV) continues despite regional lung injury. This failure to block vasoconstriction alters the repair response and leads to tissue destruction in emphysema susceptible smokers (SS) with abnormal vasoregulation. The normal response to regional hypoxia is to shunt blood towards better- ventilated regions. However, smoking induces small scale, regional infiltrates which in turn lead to local hypoxia, HPV would interfere with defense mechanisms serving to clear the irritant and thus interfere with mechanisms of repair. We have demonstrated that, in SS subjects with normal PFTs but CT evidence of early centriacinar emphysema (CAE), there is an increased heterogeneity of perfusion. This is supportive of the notion that attenuation of vasoconstriction has failed. Further, we have demonstrated a tight correlation between quantitative CT evidence of emphysema with reduced LV filling down to very small amounts of emphysema. We outline a series of experiments seeking to: 1) link increased pulmonary perfusion heterogeneity in SS subjects to the lung's response to alveolar oxygenation; 2) establish that the perfusion heterogeneity is reversible; 3) demonstrate that the response to inflammation and not just inflammation itself is a key factor in the increased heterogeneity and finally; 4) demonstrate that, by alleviating heterogeneous vasoconstriction, parenchymal hyper-density associated with smoking will clear more quickly in association with smoking cessation. With any combination of positive outcomes of this study, we will have provided new insights into disease etiology, serving to provide new targets for disease intervention and providing the tools needed for assessing outcomes.